Acquired resistance to chemotherapy is a major problem in treatment of cancer by conventional cytotoxic drugs. Tumors may initially respond well to chemotherapy but later become resistant to a variety of unrelated drugs, leading to relapse. One cause of multidrug resistance is believed to be overexpression of a transmembrane transport protein known as P-glycoprotein or MDR protein. Another cause of multidrug resistance is believed to be overexpression of a member of the ATP-binding cassette transmembrane transporter superfamily known as multidrug resistance-associated protein (MRP). This protein is overexpressed in certain tumor cell lines which are multidrug resistant but do not overexpress P-glycoprotein. Cole et al. (1992) Science 258:1650-1654; Slovak et al., (1993) Cancer Res. 53:3221-3225.
Small-cell lung cancer accounts for 20-25% of all lung cancer. Up to 90% of small-cell lung cancers respond initially to chemotherapy, but nearly all become multidrug resistant, leading to relapse. The gene encoding MRP was initially isolated from a multidrug-resistant small-cell lung cancer cell line.
Agents capable of reversing the phenomenon of multidrug resistance and thus "sensitizing" the drug resistant tumors to chemotherapy are desired. Cyclosporin A and other agents are able to reverse doxorubicin resistance in cells which overexpress MDR, but clinical use of these compounds is limited by their cytotoxicity. Further, these reversing agents do not work in cells which overexpress MRP. Antisense oligonucleotides targeted to the MDR mRNA have been used to partially reverse the multidrug resistance phenotype. Thierry et al., (1993) Biochem. Biophys. Res. Comm. 190:952-960. Others have found that complete inhibition of P-glycoprotein (MDR protein) synthesis with antisense methylphosphonate oligonucleotides leads to only a partial decrease in drug resistance. Vasanthakumar, G. and N.K. Ahmed (1989) Cancer Commun. 1:225-232.
Interference with MRP expression is desired as a means for reversing the multidrug resistance phenomenon. Interference with MRP expression is also desired for improving the efficacy of conventional methods of cancer chemotherapy, particularly of lung cancer, most particularly of small-cell lung cancer.